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Updated: May 5, 2026
A Mouse Model of Single and Repetitive Mild Traumatic Brain Injury
Published on: June 20, 2017
Severity of Repetitive Mild Traumatic Brain Injury Depends on Microglial Heme Oxygenase-1 and Carbon Monoxide
Sandra Kaiser1,2, Anna Fritsch1,2, Lena Jakob1,2
1Department of Anesthesiology & Critical Care, Medical Center-University of Freiburg, Freiburg, Germany.
Abstract:
Traumatic brain injury is one of the most common cerebral incidences worldwide. Repetitive mild traumatic brain injuries occurring, for example, in athletes or victims of abuse, can cause chronic neurodegeneration due to neuroinflammation, in which the crosstalk between reactive astrocytes and activated microglia is crucial for modulating neuronal damage. The inducible enzyme heme oxygenase-1 and its product carbon monoxide are known to be ascribed neuroprotective and anti-inflammatory properties. We caused repetitive mild traumatic brain injuries in wild-type mice compared to mice without microglial heme oxygenase-1 expression. Additionally, mice were treated daily with either air or carbon monoxide exogenously. In wild-type mice, we observed enhanced microglia activation and astrogliosis as well as vasodilation after repetitive trauma. In heme oxygenase-1 knockout mice, we observed enhanced activation of microglia and astrocytes at baseline pretrauma with a lack of an adequate inflammatory response to repetitive injury. However, the knockout led to enhanced NF-κB and IFNγ expression in the post-trauma period. Carbon monoxide exerted neuroprotection, as suggested by reduced wake-up times in mice and by beneficially altering inflammation post-traumatic brain injury. This study further underlines the crucial role of the heme oxygenase-1/carbon monoxide system in the modulation of neuronal damage and the associated neuroinflammatory response after repetitive traumatic brain injury.
Insights
Repetitive mild traumatic brain injuries trigger neuroinflammation. The heme oxygenase-1/carbon monoxide system protects against brain damage and inflammation, highlighting its therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Cellular Biology
Background:
- Traumatic brain injury (TBI) is a global health concern, with repetitive mild TBI (rmTBI) leading to chronic neurodegeneration.
- Neuroinflammation, driven by microglia and astrocyte interactions, is a key factor in neuronal damage following rmTBI.
- The heme oxygenase-1 (HO-1) enzyme and its product, carbon monoxide (CO), possess known neuroprotective and anti-inflammatory effects.
Purpose of the Study:
- To investigate the role of microglial HO-1 in the neuroinflammatory response to rmTBI.
- To evaluate the neuroprotective effects of exogenous carbon monoxide administration in a mouse model of rmTBI.
Main Methods:
- Repetitive mild TBI was induced in wild-type and HO-1 knockout mice.
- Mice were treated with either air or exogenous carbon monoxide.
- Microglia activation, astrogliosis, vasodilation, and inflammatory markers (NF-κB, IFNγ) were assessed.
Main Results:
- Wild-type mice showed increased microglia activation, astrogliosis, and vasodilation post-rmTBI.
- HO-1 knockout mice exhibited heightened baseline microglia/astrocyte activation but an impaired inflammatory response to injury.
- Carbon monoxide treatment reduced wake-up times and beneficially modulated inflammation, indicating neuroprotection.
Conclusions:
- The heme oxygenase-1/carbon monoxide pathway plays a critical role in mitigating neuronal damage after rmTBI.
- Targeting the HO-1/CO system offers a promising therapeutic strategy for managing neuroinflammation and neurodegeneration in TBI.
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